4-heteroaryl-and 4-aryl-1,4-dihydropyridine, derivatives with calcium agonist and alpha1 -antagonist activity

ABSTRACT

There are provided novel 1,4-dihydropyridine compounds, compositions containing them and methods of using them to treat congestive heart failure.

FIELD OF THE INVENTION

This invention relates to certain novel 1,4-dihydropyridines, processesfor their preparation, pharmaceutical compositions containing them, andmethods of using them to treat congestive heart failure, and moreparticularly to such 1,4-dihydropyridines having both calcium agonistand alpha₁ -antagonist activity and which are useful in the treatment ofcongestive heart failure.

BACKGROUND OF THE INVENTION

Over the past decade, dihydropyridine calcium antagonists or calciumchannel blockers have become widely known therapeutic agents havingvasodilator properties which can be used as antihypertensives andcoronary dilator agents. These compounds inhibit the entry of calciumions into cells, or its mobilization from intracellular stores. Morerecently, it has been found that small structural modifications of theseknown compounds produce dihydropyridines with effects diametricallyopposed to those of calcium channel blockers. Dihydropyridines such asBay K8644 and CGP 28392 (FIG. 1) promote an influx of calcium ions, intocells thereby producing positive inotropic and vasoconstrictor effects.Bay K8644 is more than ten times as potent as CGP 28392 as a calciumagonist. However, Bay K8644 is not useful as a cardiotonic because ofits coronary vasoconstricting properties. Therefore it is only useful asa pharmacological tool to ascertain the function of calcium entryblockers. ##STR1##

Representative of the art in the field of dihydropyridine calciumagonists are U.S. Pat. No. 4,248,873 (Bossert et al.) issued Feb. 3,1981, European Patent Application 0071819 published Feb. 16, 1983(Boshagen et al.), U.S. Pat. No. 4,537,881 (Franckowiah et al.) issuedAug. 27, 1985 and U.S. Pat. No. 4,532,248 issued Jul. 30, 1985 whichdescribes dihydropyridine calcium agonists which contain an amino groupin the 2-position. Literature references include M. Schram, et al.,Nature, 303, 535 (1983); M. Schram, et al., Arzneim-Forsch., 33, 1268(1983); P. Erne, et al., Biochem. Biophys. Res. Commun., 118, 842(1984).

Combining calcium agonist properties and alpha₁ -adrenergic blockingproperties in a single molecular structure provides a new and attractiveprinciple for the treatment of congestive heart failure. The combinationof these two types of activities affords a novel class of cardiotonicswhich have cardiac stimulatory effects in combination with pronouncedvasodilator properties. The detrimental vasoconstricting propertieswhich are normally associated with dihydropyridine calcium agonists areminimized by the alpha₁ -adrenergic blocking properties which causedilation of the peripheral vasculature. Applicants are not aware of anyreferences that describe the combination of these actions in a singlecompound, other than co-assigned U.S. Pat. No. 4,868,181 (Johnson etal.) issued Sep. 19, 1989.

SUMMARY OF THE INVENTION

According to the present invention there is provided novel1,4-dihydropyridine derivatives of the general formula (I) which possessboth calcium channel promoting activity and alpha₁ -adrenergic blockingproperties and are useful in the treatment of congestive heart failure.These compounds have the formula: ##STR2## or a pharmaceuticallyacceptable salt thereof or an optically active isomer or N-oxide thereofwherein:

R² and R⁶ independently are alkyl of 1-4 carbon atoms, CN, CH₂ OH or CH₂OCH₂ CH₂ NH₂ ;

R³ independently is NO₂, H, CN, CONH₂, or taken together with R² is##STR3##

Cy, when R⁵ is CHO, COCH₃, CO₂ CH₂ CHOHC₆ H₅, CO₂ CH(OCH₃)C₆ H₅, NO₂,CONHC₆ H₅ or an alkyl ester of 1-10 carbon atoms, is: ##STR4##

R¹ and R⁹ independently are H, alkyl of 1-4 carbon atoms, haloalkyl of1-4 carbon atoms, alkoxy of 1-10 carbon atoms, halogen or NO₂ ;

Cy, when R⁵ is COR⁷, CO₂ R⁷, is: 3-, or 4-pyridinyl; 2- or 3-furanyl; 2-or 3-thienyl, 4-, or 5-thiazolyl, 2-, 4-, or 5-pyrimidinyl or ##STR5##

X is SO, SO₂, NR⁴, O, S or N→O;

Y is CH₂, ##STR6##

Z is ##STR7##

R⁴ is H or an alkyl group of 1-4 carbon atoms;

R⁷ is ##STR8##

A is a straight or branched alkyl, alkenyl, or alkynyl chain or--(CH₂)_(n) CHOHCH₂ --;

R¹⁰ is ##STR9## or 2-, 3-, or 4-pyridinyl; 2-, or 4-pyrimidinyl; or2-pyrazinyl;

R⁸ is ##STR10##

Ar is phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of: alkyl of 1-4 carbonatoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms,halogen, or NO₂, provided that Ar is not 4-fluorophenyl;

Q is (CH₂)q, (CH₂)_(n) O, (CH₂)_(n) NH or (CH₂)_(n) S;

n is independently 1-4;

p is 1 to 10;

q is 0-2; and

r is 1 to 10, with the following proviso: ##STR11## when Cy is and X isO, S or NH, then, R⁷ cannot be --(A)_(r) --NH--Q--Ar, where A is asdefined above;

R⁸ cannot be Ar; and

R¹⁰ cannot be 2-, 3-, or 4-pyridinyl or 2-, or 4-pyrimidinyl.

The compounds of the present invention can exist as optical isomers andboth the racemates as well as the individual optical isomer whichconfers agonist activity are within the scope of the present invention.The racemic mixtures can be separated into their individual isomers bywell known techniques such as the separation of the diastereomeric saltsformed with optically active acids, followed by conversion back to theoptically active 1,4-dihydropyridine.

Also provided are pharmaceutical compositions comprising a suitablepharmaceutical carrier and a compound of formula (I) and methods ofusing the compounds of formula (I) to treat congestive heart failure.

Further provided are processes for preparing compounds of formula (I),which processes will be described in detail hereinafter.

PREFERRED EMBODIMENTS

Preferred compounds are those of formula (I) wherein:

(A)

(1) R² is CH₃ ; and/or

(2) R³ is NO₂ ; and/or ##STR12## (3) Cy is (4) R⁵ is an alkyl ester of1-4 carbon atoms, wherein:

(a) R¹ is H; and/or

(b) Y is CH₂ and/or

(c) R⁷ is ##STR13## wherein (i) A is --(CH₂)_(p) -- where p is 1 to 5;and/or

(ii) R⁸ is Ar where Ar is phenyl optionally monosubstituted with OCH₃,CH₃, or Cl; or R⁸ is ##STR14## (iii) R¹⁰ is 2- or 4-pyrimidinyl. (B)

(1) R² is CH₃ ; and/or

(2) R³ is NO₂ ; and/or ##STR15## (3) Cy is (4) R⁵ is an alkyl ester of1-4 carbon atoms, wherein;

(a) R¹ is H; and/or

(b) X is O; and/or

(c) R⁷ is ##STR16## wherein: (i) A is --(CH₂)_(p) -- (p=1-5); and/or

(ii) R⁸ is selected from the group consisting of: ##STR17## (C) (1) R²is CH₃ ; and/or

(2) R³ is NO₂ ; and/or ##STR18## (3) Cy is (4) R⁵ is an alkyl ester of1-4 carbon atoms, wherein;

(a) R¹ is H; and/or

(b) X is SO₂ ; and/or

(c) R⁷ is ##STR19## wherein: (i) A is --(CH₂)_(p) -- (p=1-5); and/or

(ii) R⁸ is Ar, where Ar is phenyl optionally monosubstituted with OCH₃,CH₃ or Cl, or is selected from the group consisting of: ##STR20## (D)(1) R² is CH₃ ; and/or

(2) R³ is NO₂ ; and/or

(3) Cy is 2- or 3-furanyl; 2- or 3-thienyl; 3-pyridinyl; ##STR21## (4)R⁵ is CO₂ R⁷ ; where; (a) R⁷ is ##STR22## wherein: (i) A is --(CH₂)_(p)-- (p=1-5); and/or

(ii) R⁸ is Ar where Ar is phenyl optionally monosubstituted with OCH₃,CH₃, or Cl; and/or

(iii) R¹⁰ is 2- or 4-pyrimidinyl.

Specifically Preferred Compounds

(1) 14-Dihydro-4-(2-{5-[4-(2-methoxyphenyl)-1-piperazinyl]pentyl}-3-furanyl)-2,6-dimethyl-5-nitro-3-pyridinecarboxylicacid, methyl ester

(2)4-(4-Benzofurazanyl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylicacid, {4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl} ester

(3)1,4-Dihydro-2,6-dimethyl-5-nitro-4-(3-pyridinyl)-3-pyridinecarboxylicacid, {4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl} ester

(4) 4-(3-Furanyl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylicacid, {2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl} ester

(5) 4-(3-Furanyl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylicacid, {2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl} ester

(6)1,4-Dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecarboxylicacid, {4-[4-(2-methoxyphenyl)1-piperazinyl]butyl} ester

(7)1,4-Dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecarboxylicacid, {4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl} ester

(8) 1,4-Dihydro-2,6-dimethyl-5-nitro-4-(3-thienyl)-3-pyridinecarboxylicacid, {2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl} ester

(9) 1,4-Dihydro-2,6-dimethyl-5-nitro-4-(3-thienyl)-3-pyridinecarboxylicacid, {2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl} ester

(10) 4-(3-Furanyl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylicacid, {4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl} ester

(11) 4-(2-Furanyl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylicacid, {4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl} ester

(12) 1,4-Dihydro-2,6-dimethyl-5-nitro-4-(2-thienyl)-3-pyridinecarboxylicacid, {2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl} ester

(13)1,4-Dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecarboxylicacid, {2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl} ester

(14)1,4-Dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecarboxylicacid, {2-[4-(2-pyrimidinyl) 1-piperazinyl]ethyl} ester

DETAILED DESCRIPTION OF THE INVENTION Synthesis

The dihydropyridines of the general formula (I), can be prepared by theprocesses illustrated below. It is understood in all of these processesthat R¹ -R¹⁰, Ar, X, Y, A, p, r, Q, n, q are as defined above. MethodsA-F are substantially the same as described in commonly assigned U.S.Pat. No. 4,868,181 which is herein incorporated by reference.

Compounds of the formula CyCHO (2) are commercially available, or may beprepared by methods described in the literature. The heterocyclicaldehydes used as intermediates are available by methods described instandard works on heterocyclic chemistry such as Katritzsky and Rees,Comprehensive Heterocyclic Chemistry, vols. 2-5, Pergamon Press, N.Y.,1984. In some instances, the preparation of the hydroxymethyl compoundsare described in the literature. These can be converted to thecorresponding aldehydes by known methods, such as oxidation withmanganese dioxide, or dimethysulfoxide activated with oxalyl chloride.

Compounds of the formula 6 may be prepared according to Method 1, whereX" is NR⁴, O, or S, and R¹² is CO₂ R⁴ or CH₂ OH (or a protectedalcohol). Compound 3 is alkylated with an appropriate connector chain 4to give compound 5. This reaction is carried out in the presence of anaromatic hydrocarbon such as benzene, toluene, etc., a halogenatedhydrocarbon such as dichloromethane, carbon tetrachloride, etc., anether such as THF, DME, etc., or an aprotic solvent such asacetonitrile, DMF, etc., in the presence of a base such as potassiumcarbonate, sodium carbonate, sodium bicarbonate, or sodium hydride, at atemperature in the range of -20° C. to 200° C., preferably of 25° C. to150° C. Separation of the desired product from the reaction mixture iseffected by conventional operations such as filtration, concentration,extraction, column chromatography, recrystallization, etc. ##STR23##

Compounds of the formulas 7, 8, 9, and 10 may be purchased commercially,or prepared according to the methods described by S. F. Campbell, etal., J. Med. Chem., 30, 49, 999, 1794 (1987), and by other methodsreported in the literature. ##STR24##

Compounds of the formula 13 may be prepared according to Method 2.Compound 11 (prepared according to Methods A-D) is converted to thecarboxylic acid with a fluoride source, such as tetrabutylammoniumfluoride or hydrogen fluoride. Treatment with 1,1'-carbonyldiimidazoleprovides the activated imidazolide 12, which may be reacted withalcohols of the type R⁷ OH to produce 13. ##STR25##

As shown in Method 3, compounds of the formulas 15 and 17 may beprepared by reacting compounds of the formulas 14 and 16 with amines 7or 8 or 9 or 10, respectively. The reaction is carried out by reacting14 or 16 with amines 7 or 8 or 9 or 10 in a molar ratio of 1.0:1.0 to1.0:4.0 in the presence of a base such as potassium carbonate, sodiumcarbonate, sodium bicarbonate, triethylamine, or sodium hydroxide. Thereaction is performed in the presence of an alcoholic solvent such asmethanol, ethanol, i-propanol or n-butanol, an aromatic hydrocarbon suchas benzene or toluene, an ether such as tetrahydrofuran (THF) ordioxane, a halogenated hydrocarbon such as chloroform or carbontetrachloride, an aprotic polar solvent such as acetonitrile,dimethylformamide (DMF) or dimethylsulfoxide (DMSO), or the like at atemperature in the range of room temperature to 200° C., preferably atabout 25° C.-110° C. Separation of the desired product from the reactionmixture is effected by conventional techniques such as filtration,concentration, extraction, column chromatography, recrystallization,etc.

This method is also applicable for compounds of the Formula 16, where Yor Z is substituted for X. ##STR26##

Where X is NR⁴ or S, 17 can be oxidized to R⁴ N→O or SO or SO₂,respectively, with an oxidizing agent such as hydrogen peroxide,peracetic acid, m-chloroperbenzoic acid, etc.

Compounds of the formula 19, where R¹³ is S or O, (Method 4) may beprepared according to procedures described in the literature, such as I.Sircar, et al., Tetrahedron Lett. 29, 6835 (1988) and U.S. Pat. No.4,642,310, issued Feb. 10, 1987. ##STR27##

The above preparation processes are given merely for illustration. Thepreparation of the compounds of the formula (I) is not limited to theseprocesses, but any modification of these processes can be applied in thesame manner to the preparation of the compounds according to theinvention.

A resulting basic compound can be converted into a corresponding acidaddition salt by reacting it with an inorganic or organic acid as iswell known to one skilled in the art. Therapeutically useful acidsinclude, for example, inorganic acids, such as hydrochloric,hydrobromic, sulfuric, phosphoric or nitric, or organic acids, such asformic, acetic, propionic, succinic, maleic, fumaric, tartaric orascorbic acid.

The compounds of this invention and their preparation can be understoodfurther by the following examples, but should not constitute alimitation thereof. In these examples, unless otherwise indicated, alltemperatures are in degrees Celsius and parts and percentages are byweight.

EXAMPLE 1

Part A; 2-(5-Chloropentyl)-3-furanmethanol: To a solution of3-furanmethanol (3.56 g) in THF (200 ml) at -20° C., was addedn-butyllithium (50 ml of 1.6M in hexane). The solution was kept at 0° C.for 4 hrs., then 5-chloro-1-iodopentane (8.37 g) was added. The mixturewas stirred at room temperature for 4 days, after which water (500 ml)and ether (500 ml) were added. The organic layer was separated and driedover magnesium sulfate and the solvent was removed by rotary evaporationto give an oil. Purification by column chromatography on silica gel,using hexane:ethyl acetate (1:1) as the eluent provided the pureproduct, 5.6 g. ¹ H-NMR (CDCl₃) ∂ 1.50 (m, 2H); 1.67 (m, 2H); 1.80 (m,2H); 2.64 (t, 2H, J=7Hz); 3.52 (t, 2H, J=7Hz); 4.46 (s, 2H); 6.04 (s,1H); 6.36 (s, 1H).

Part B; 2-(5-Chloropentyl)-3-furanaldehyde: To a 500 ml 4-neckround-bottom flask fitted with mechanical stirrer, thermowell, andaddition funnel, under a nitrogen atmosphere, was added 7.4 ml of oxalylchloride and 150 ml of dichloromethane. The reaction was cooled to -78°C. with a dry ice/acetone bath. Then 12.58 ml of distilleddimethylsulfoxide in 38 ml of dichloromethane was added dropwise,maintaining the reaction temperature below -65° C. After the additionwas complete, 15 g of 2-(5-chloropentyl)-3-furanmethanol was added in 74ml of dichloromethane. After addition was complete, the mixture wasstirred for 30 min., then 52 ml of triethylamine was added. The bath wasallowed to warm gradually to room temperature, and stirred overnight atthis temperature. The reaction mixture was poured into a 1 liter flaskcontaining a stirring mixture of 310 g of crushed ice and 47 ml of 1NHCl. After stirring for 30 min., the mixture was extracted withdichloromethane (3×100 ml). The organic solution was dried overmagnesium sulfate, filtered and concentrated to a brown oil. The productwas further purified by column chromatography on silica gel, elutingwith 10% ethyl acetate in hexane to give 12.75 g of the purified productas an oil. ¹ H-NMR (CDCl₃) ∂ 1.52 (m, 2H); 1.79 (m, 4H); 2.98 (t, 2H,J=7Hz); 3.54 (t, 2H, J=7Hz); 6.70 (d, 1H, J=2Hz); 7.33 (d, 1H, J-2Hz);9.95 (s, 1H).

Part C;1,4-Dihydro-4-[2-(5-chloropentyl)-3-furanyl]-2,6-dimethyl-5-nitro-3-pyridinecarboxylicacid, methyl ester: A mixture of 2-(5-chloropentyl)-3-furanaldehyde(10.2 g), nitroacetone (7.9 g), and methyl 3-aminocrotonate (5.9 g) in250 ml of ethanol was heated at reflux for 18 hrs. After removal of thesolvent by rotary evaporation, the residue was purified via columnchromatography on silica gel, eluting with 30% petroleum ether indiethyl ether, to give a yellow solid. Recrystallization fromchloroform/diethyl ether produced yellow crystals, 3.2 g, m.p. 133°-135°C. ¹ H-NMR (CDCl₃) ∂ 1.65 (m, 4H); 1.87 (m, 2H); 2.36 (s, 3H); 2.52 (s,3H); 2.78 (m, 2H); 3.56 (t, 2H, J=7Hz); 3.69 (s, 3H); 5.29 (s, 1H); 5.98(s, 1H); 6.07 (d, 1H, J=1Hz); 7.14 (d, 1H, J=1Hz). Mass spectrum: 383(M+H). IR (KBr): 3311, 2952, 1706, 1654, 1491, 1450, 1220 cm⁻¹.

Part D;1,4-Dihydro-4-(2-{5-[4-(2-methoxyphenyl)-1-piperazinyl]pentyl}-3-furanyl)-2,6-dimethyl-5-nitro-3-pyridinecarboxylic acid, methyl ester: A mixtureof1,4-dihydro-4-[2-(5-chloropentyl)-3-furanyl]-2,6-dimethyl-5-nitro-3-pyridinecarboxylicacid, methyl ester (1.0 g), 0.9 g of 1-(2-methoxyphenyl)piperazine, 75mg of sodium iodide, and 0.4 g of sodium bicarbonate in 100 ml ofacetonitrile was heated at reflux for 6.5 hrs., then stirred overnightat room temperature. The solvent was removed by rotary evaporation, andthe residue was partitioned between dichloromethane and water. Theaqueous layer was washed with dichloromethane (2×100 ml), the organiclayers combined, washed with water, dried over magnesium sulfate,filtered, and concentrated. The crude product was purified by columnchromatography, eluting with 5% methanol in dichloromethane. The product(Ex. No. 1, Table 1) was isolated as an orange solid, 1.07 g., m.p.94°-105° C. ¹ H-NMR (CDCl₃) ∂ 1.45 (m, 2H); 1.69 (m, 6H); 2.37 (s, 3H):2.51 (m, 1H); 2.77 (m, 5H); 3.28 (m, 4H); 3.68 (s, 3H); 3.87 (s, 3H);5.30 (s, 1H); 6.11 (d, 1H, J= 2Hz); 6.30 (br. s., 1H); 6.95 (m, 4H);7.14 (d, 1H, J=2Hz). IR (KBr) 2942, 1709, 1651, 1501, 1317, 1225 cm⁻¹.Mass Spectrum: 539 (M+1), 211 (DHP nucleus). HRMS: Calcd: 538 2791;Found: 538.2795

EXAMPLE 53

Part A; 1,4-Dihydro-2,6-dimethyl-5-nitro-4-(3-pyridinyl)-3-pyridinecarboxylic acid, (4-chlorobutyl)ester: A mixture of nitroacetone (3.41 g), 3-pyridinecarboxaldehyde(2.36 g), and (4-chlorobutyl)-3-aminocrotonate (4.22 g) in 100 mlethanol was heated to reflux for 4 hrs., then stirred at roomtemperature for 16 hrs. After removal of the solvent by rotaryevaporation, the residue was purified via column chromatography onsilica gel, eluting with 15% methanol in ethyl acetate, to give a yellowsolid, 4.13 g, m.p. 153°-156° C. (dec). ¹ H-NMR (CDCl₃) ∂ 1.72 (m, 4H);2.37 (s, 3H); 2.52 (s, 3H); 3.50 (t, 2H, J=6Hz); 4.10 (t, 2H, J=6Hz);5.38 (s, 1H); 7.26 (dd, 1H, J=8, 5Hz); 7.77 (dd, 1H, J=2, 8Hz); 8.01 (s,1H); 8.43 (dd, 1H, J=2, 5Hz); 8.50 (d, 1H, J=2Hz). Mass spectrum: 366(M+H).

Part B;1,4-Dihydro-2,6-dimethyl-5-nitro-4-(3-pyridinyl)-3-pyridinecarboxylicacid, {4-4-(2-pyrimidinyl)-1-piperazinylbutyl} ester: To a 100 ml 3-neckround-bottom flask fitted with mechanical stirrer, reflux condenser, andthermowell, under a nitrogen atmosphere, was added 1.0 g of1,4-dihydro-2,6-dimethyl-5-nitro-4-(3-pyridinyl)-3-pyridinecarboxylicacid, (4-chlorobutyl) ester, 80 ml of DME, 1.79 g of1-(2-pyrimidinyl)piperazine, 0.10 g of sodium iodide, and 0.5 g ofsodium bicarbonate. The reaction mixture was heated at reflux overnight.The solvent was removed by rotary evaporation, and the residue waspartitioned between dichloromethane and water. The aqueous layer waswashed with dichloromethane (2×200 ml), the organic layers combined,washed with water, dried over magnesium sulfate, filtered, andconcentrated. The crude product was purified by column chromatography,eluting with 10% methanol in ethyl acetate. The product (Ex. No. 53,Table 2) was isolated as an orange solid, 0 79 g, m.p. 1.55°-160° C.(dec). ¹ H-NMR (CDCl₃) ∂ 1.40-1.66 (m, 4H); 2.33 (m, 2H); 2.40 (s, 3H);2.46 (m, 4H); 2.53 (s, 3H); 3.79 (m, 4H); 4.10 (t, 2H, J=6Hz); 5.40 (s,1H); 6.48 (t, 1H, J=6Hz); 6.96 (s, 1H); 7.23 (m, 1H); 7.73 (m, 1H); 8.31(d, 2H, J=6Hz); 8.43 (m, 1H); 8.54 (d, 1H, J=1Hz). IR (KBr): 3189, 2944,1706, 1650, 1587, 1548, 1500, 1360, 1225 cm⁻¹. Mass Spectrum 494 (M+1),522 (M+29), 219 (C₁₂ H₁₉ N₄).

EXAMPLE 77

Part A; 1,4-Dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecarboxylic acid,(2-chloroethyl) ester: A mixture of nitroacetone (6.82 g),1-methyl-2-pyrrolecarboxaldehyde (4.80 g),(2-chloroethyl)-3-aminocrotonate (7.20 g) and 10 g molecular sieves in200 ml ethanol was stirred at room temperature for 4 days. After removalof the solvent by rotary evaporation, the residue was purified viacolumn chromatography on silica gel, eluting with 30% petroleum ether indiethyl ether, to give a brown solid, 2.36 g. ¹ H-NMR (CDCl₃) ∂ 2.49 (s,3H); 2.52 (s, 3H); 3.66 (t, 2H, J=6Hz); 3.87 (s, 3H); 4.35 (t, 2H,J=6Hz); 5.29 (s, 1H); 5.89 (m, 1H); 5.97 (m, 1H); 6.16 (br. s, 1H); 6.43(m, 1H).

Part B;1,4-Dihydro-2,6-dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecarboxylicacid, {2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl} ester: A mixture of1,4-dihydro-2,6dimethyl-4-(1-methyl-1H-pyrrol-2-yl)-5-nitro-3-pyridinecarboxylic acid,(2-chloroethyl) ester 1.36 g, 1.54 g of 1-(2-methoxyphenyl)piperazine,133 mg of sodium iodide, and 0.7 g of sodium bicarbonate in 100 ml ofDME was heated at reflux for 4 days. The solvent was removed by rotaryevaporation, and the residue was partitioned between dichloromethane andwater. The aqueous layer was washed with dichloromethane (2×100 ml), theorganic layers combined, washed with water, dried over magnesiumsulfate, filtered, and concentrated. The crude product was purified bycolumn chromatography, eluting with ethyl acetate. The product (Ex No.77, Table 2) was isolated as an orange solid, 0.71 g. ¹ H-NMR (CDCl₃) ∂2.38 (s, 3H); 2.51 (s, 3H); 2.65 (m, 6H); 3.05 (s, 4H); 3.86 (s, 6H);4.25 (t, 2H, J=6Hz); 5.30 (s, 1H); 5.87 (t, 1H, J=2Hz); 5.88 (s, 1H);5.96 (t, 1H, J=3Hz); 6.43 (t, 1H, J=3Hz); 6.92 (m, 4H). IR (KBr): 3318,3096, 2941, 2819, 1687, 1500, 1312, 1102, 1014, 750 cm⁻¹. Mass Spectrum:496 (M+1), 524 (M+29).

Other compounds which can be prepared by such procedures and proceduresdescribed in the synthesis disclosure are illustrated by the structuresrepresented in Tables 1 and 2. These Tables are intended to illustratethe invention, but not limit its breadth.

    TABLE 1      ##STR28##      (I)      Ex. No. Cy R.sup.2 R.sup.3 R.sup.5 R.sup.6 mp °C.             1      ##STR29##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3 94-105.sup.a      2     ##STR30##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3 105-8.sup.b      3     ##STR31##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3 123.sup.c      4     ##STR32##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3 206.sup.d      5     ##STR33##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3 97-111.sup.e      6     ##STR34##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3 182-6.sup.f      7     ##STR35##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3 164-6.sup.g      8     ##STR36##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3 97-105.sup.h      9     ##STR37##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3 80-84.sup.i      10     ##STR38##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3 66-69.sup.j      11     ##STR39##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3 glassysolid.sup.k  12      ##STR40##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3      13     ##STR41##      CH.sub.3 NO.sub.2 CO.sub.2 C.sub.2 H.sub.5 CH.sub.3           14     ##STR42##      ##STR43##      CO.sub.2 CH.sub.3 CH.sub.3            15     ##STR44##      C.sub.2 H.sub.5 NO.sub.2 CO.sub.2 CH.sub.3 C.sub.2 H.sub.5      16     ##STR45##      CH.sub.3 CN CO.sub.2 CH.sub.3 CH.sub.2 OH      17     ##STR46##      CH.sub.3 H CO.sub.2 C.sub.3 H.sub.7 CH.sub.3      18     ##STR47##      CH.sub.3 CONH.sub.2 CO.sub.2 CH.sub.3 CH.sub.3      19     ##STR48##      CH.sub.3 NO.sub.2 CO.sub.2 C.sub.2 H.sub.5 CH.sub.3      20     ##STR49##      C.sub. 3 H.sub.7 H CO.sub.2 CH.sub.3 CH.sub.3      21     ##STR50##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3      22     ##STR51##      CN CONH.sub.2 CO.sub.2 CH.sub.3 CH.sub.3      23     ##STR52##      CH.sub.2 OH NO.sub.2 CHO CH.sub.3      24     ##STR53##      CH.sub.3 NO.sub.2 COCH.sub.3 CH.sub.3      25     ##STR54##      CH.sub.3 CN CO.sub.2 C.sub.2 H.sub.5 CH.sub.3      26     ##STR55##      CH.sub.3 CONH.sub.2 COCH.sub.3 CH.sub.3      27     ##STR56##      C.sub.3 H.sub.7 NO.sub.2 CO.sub.2 CH.sub.2 CHOHC.sub.6 H.sub.5 CH.sub.3      28     ##STR57##      CH.sub.3 NO.sub.2 CO.sub.2 C.sub.3 H.sub.7 CH.sub.3           29     ##STR58##      ##STR59##      CO.sub.2 CH.sub.3 CH.sub.3            30     ##STR60##      CN CN CO.sub.2 CH.sub.3 CH.sub.3      31     ##STR61##      CH.sub.3 CONH.sub.2 CO.sub.2 C.sub.2 H.sub.5 CH.sub.3      32     ##STR62##      CH.sub.2 OH H CO.sub.2 CH.sub.3 C.sub.2 H.sub.5      33     ##STR63##      CH.sub.3 CN CO.sub.2 CH.sub.3 CH.sub.3      34     ##STR64##      NH.sub.2 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3      35     ##STR65##      C.sub.2 H.sub.5 NO.sub.2 CO.sub.2 CH.sub.3 C.sub.2 H.sub.5      36     ##STR66##      CH.sub.3 NO.sub.2 COCH.sub.3 CH.sub.3      37     ##STR67##      CH.sub.3 H CO.sub.2 CH.sub.3 CH.sub.3      38     ##STR68##      CH.sub.2 OH NO.sub.2 CHO CH.sub.3      39     ##STR69##      CH.sub. 3 NO.sub.2 CONHC.sub.6 H.sub.5 CH.sub.3      40     ##STR70##      CH.sub.3 CONH.sub.2 CO.sub.2 CH.sub.3 CH.sub.3           41     ##STR71##      ##STR72##      CO.sub.2 CH.sub.3 C.sub.2 H.sub.5            42     ##STR73##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3      43     ##STR74##      CH.sub.3 NO.sub.2 CHO CH.sub.3      44     ##STR75##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.2 CHOHC.sub.6 H.sub.5 CH.sub.3  45      ##STR76##      CH.sub.3 NO.sub.2 CO.sub.2 C.sub.2 H.sub.5 CH.sub.3      46     ##STR77##      CH.sub.3 CN CO.sub.2 CH.sub.3 C.sub.2 H.sub.5            47     ##STR78##      ##STR79##      CO.sub.2 C.sub.3 H.sub.7 CH.sub.3            48     ##STR80##      CH.sub.3 NO.sub.2 CO.sub.2 CH.sub.3 CH.sub.3      49     ##STR81##      C.sub.2 H.sub.5 CONH.sub. 2 CO.sub.2 C.sub.2 H.sub.5 CH.sub.3       50      ##STR82##      ##STR83##      CO.sub.2      CH.sub.3 CH.sub.3     Footnotes for Table 1 .sup.a see text for spectral data. .sup.b1     H-NMR(200 MHz, CDCl.sub.3)∂1.44(m, 2H); 1.61(m, 8H);     2.37(s, 3H); 2.45(m, 2H); 2.51(s, 3H); 2.73(m, 2H); 3.70(s, 3H); 3.88(m,     4H); 5.32(s, 1H); 6.12(s, 2H); 6.52(m, 1H); 7.00(m, 1H); 7.17(s, 1H);     7.53(s, 1H). IR (KBr): 2943, 1707, 1616, 1490, 1436, 1225 cm.sup.-1.     Mass Spectrum: 527(M + 1), 555(M + 29). m.p.: 105-108° C. HRMS:     Calcd: 526.2427; Found: 526.2426; .sup.c1      H-NMR(200 MHz, CDCl.sub.3)∂1.68-2.05(m, 4H); 2.24(s, 3H);     2.46(t, 2H, J=7Hz); 2.54(s, 3H); 2.65(m, 4H); 3.08(m, 4H); 3.35(m, 1H);     3.61(s, 3H); 3.85(s, 3H); 6.57(s, 1H); 6.67(s, 1H); 6.83-6.99(m, 4H);     .sup.d1 H-NMR(200 MHz, d.sub.6 -DMSO)∂1.95(s, 4H); 2.35(s,     3H); 2.57(s, 3H); 2.89(m, 2H); 3.14-3.22(m, 6H); 3.49-3.62(m, 7H);     3.81(s, 3H); 5.76 (s, 1H); 6.92-7.06(m, 4H); 7.31-7.36(m, 1H); 7.43-7.52(     m, 2H); 7.87-7.90(m, 1H); 10.24(s, 1H). .sup.e1      H-NMR(200 MHz, CDCl.sub.3)∂1.56(m, 4H); 1.80(t, 2H,     J=7Hz); 2.31(s, 3H); 2.48(s, 3H); 2.54(m, 6H); 3.59(s, 3H); 3.84(m, 4H);     3.95 (t, 2H, J=7Hz); 5.64(s, 1H); 6.36(s, 1H); 6.50(m, 1H); 6.85(m, 2H);     7.00(d, 1H, J=2Hz); 7.14(m, 1H); 7.29(m, 1H); 7.48(s, 1H). IR(KBr):     2945, 1706, 1619, 1491, 1307, 1225 cm.sup.-1. Mass Spectrum: 553(M + 1),     249, 211. m.p.: 97-111° C. HRMS: Calcd: 552.2584; Found: 552.2577     .sup.f1 H-NMR(200 MHz, CDCl.sub.3)∂1.50(m, 2H); 1.91(m,     2H); 2.05(m, 4H); 2.31(m, 2H); 2.39(s, 3H); 2.62(s, 3H); 2.80(s, 3H);     3.04(m, 2H); 3.58(s, 3H); 3.62(m, 2H); 3.83(t, 2H, J=6Hz); 5.51(s, 1H);     6.81(m, 2H); 7.12(m, 1H); 7.32(m, 6H); 8.56(s, 1H). IR(KBr): 2942, 1707,     1651, 1494, 1307 1224 cm.sup.-1. Mass Spectrum: 534(M + 1), 562(M + 29).     m.p.: 182-6° C. HRMS: Calcd: 533.2890; Found: 533.2879; .sup.g1     H-NMR(200 MHz, CDCl.sub.3)∂1.55(m, 4H); 1.78(M, 2H);     2.31(s, 3H); 2.43(m, 2H); 2.49(s, 3H); 2.57(m, 4H); 3.60(s, 3H); 3.65(m,     4H); 3.96(t, 2H, J=6Hz); 5.64(s, 1H); 6.55(s, 1H); 6.77(m, 1H); 6.82(m,     1H); 6.91(d, 1H, J=10Hz); 7.11(m, 1H); 7.22(d, 1H, J=10Hz); 7.29(m, 1H).     IR(KBr): 2944, 1708, 1653, 1586, 1493, 1442, 1309, 1224 cm.sup.-1. Mass     Spectrum: 571(M + 1), 599(M + 29). m.p.: 164-166° C. .sup.h1     H-NMR(200 MHz, CDCl.sub.3)∂1.38(d, 6H, J=6Hz); 1.51-1.83(m,     6H); 2.32(s, 3H); 2.43(m, 2H); 2.49(s, 3H); 2.60(t, 4H, J=5Hz); 3.54(t,     4H, J=5Hz); 3.60(s, 3H); 3.92(t, 2H, J=6Hz); 5.42(m, 1H); 5.62(s, 1H);     6.29(m, 1H); 6.79(d, 1H, J=9Hz); 6.81(m, 2H); 7.02(d, 1H, J=9Hz);     7.13(m, 1H); 7.27(m, 1H). IR(KBr): 3312, 2943, 1707, 1651, 1444, 1306,     1224 cm.sup.-1. Mass Spectrum: 595(M + 1, 623(M + 29), 548, 563, 593.     m.p.: 97-105° C. HRMS: Calcd: 594.3166; Found: 594.3153; .sup.i1     H-NMR(200 MHz, CDCl.sub.3)∂1.46-1.66(m, 4H); 1.66-1.86(m,     2H); 2.31(s, 3H); 2.36-2.59(m, 6H); 2.46(s, 3H); 3.50-3.86(m, 4H);     3.60(s, 3H); 3.96(t, 2H, J=7Hz); 4.33(dd, 1H, J=8, 12Hz); 4.50(dd, 1H,     J=2, 12Hz); 4.85(dd, 1H, J=2, 8Hz); 5.66(s, 1H); 6.22(s, 1H); 6.73-     6.96(m, 6H); 7.07-7.26(m, 2H). IR(KBr): 3629, 3309, 2943, 2867, 1706,     1648, 1494, 1307, 1269, 1225, 1101, 1016, 751 cm.sup.-1. Mass Spectrum:     621(M + 1), 649(M + 29). m.p.: 80-84° C. .sup.j1 H-NMR(200 MHz,     CDCl.sub.3)∂1.52-1.66(m, 4H); 1.78-1.85(m, 2H); 2.32(s,     3H); 2.42(m, 2H); 2.48(s, 3H); 2.58(t, 4H, J=5Hz); 3.60(s, 3H); 3.61(m,     4H); 3.96(t, 2H, J=7Hz); 5.64(s, 1H); 6.16(s, 1H); 6.79(m, 1H); 6.83(m,     1H); 7.12(m, 1H); 7.26(m, 1H); 7.85(d, 1H, J=3Hz); 8.07(m, 1H); 8.14(d,     1H, J=1Hz). IR(KBr): 3310, 3078, 2944, 1707, 1492, 1380, 1313, 1222,     1016 cm.sup.-1. Mass Spectrum: 537(M + 1), 565(M +      29). m.p.: 66-69° C. HRMS: Calcd: 536.2747; Found: 536.2735.     .sup.k1 H-NMR(200 MHz, CDCl.sub.3)∂1.03(t, 3H, J=6Hz);     1.50-1.66(m, 4H); 1.73-1.86(m, 4H); 2.30(s, 3H); 2.43(m, 2H); 2.46(s,     3H); 2.53(m, 4H); 3.61(m, 4H), 3.63(s, 3H); 3.96(t, 2H, J=7Hz); 4.24(t,     2H, J=6Hz); 5.66(s, 1H); 5.82(s, 1H); 6.40(s, 1H); 6.79-6.89(m, 2H);     7.07-7.20(m, 1H); 7.28(m, 1H); 8.60(s, 1H). IR(KBr): 3316, 3094, 2936,     1708, 1593, 1540, 1493, 1380, 1306, 1220, 1013, 750 cm.sup.-1. Mass     Spectrum: 595(M +  1), 623(M + 29). HRMS: Calcd: 593.3087; Found:     593.3031.

                                      TABLE 2                                     __________________________________________________________________________     ##STR84##                                                   (I)              Ex.                                                                           No.                                                                              Cy         R.sup.2                                                                            R.sup.3                                                                            R.sup.5                     R.sup.6                                                                            mp                   __________________________________________________________________________                                                             °C.           51                                                                                ##STR85## CH.sub.3                                                                           NO.sub.2                                                                            ##STR86##                  CH.sub.3                                                                           glassy solid.sup.                                                             a                    52                                                                                ##STR87## CH.sub.3                                                                           NO.sub.2                                                                            ##STR88##                  CH.sub.3                                                                           155-160.sup.b        53                                                                                ##STR89## CH.sub.3                                                                           NO.sub.2                                                                            ##STR90##                  CH.sub.3                                                                           155-160.sup.c                                                                 (dec)                54                                                                                ##STR91## CH.sub.3                                                                           NO.sub.2                                                                            ##STR92##                  CH.sub.3                                                                            77-80.sup.d         55                                                                                ##STR93## CH.sub.3                                                                           NO.sub.2                                                                            ##STR94##                  CH.sub.3                                                                            51-61.sup.e         56                                                                                ##STR95## CH.sub.3                                                                           NO.sub.2                                                                            ##STR96##                  CH.sub.3                                                                            50-54.sup.f         57                                                                                ##STR97## CH.sub.3                                                                           NO.sub.2                                                                            ##STR98##                  CH.sub.3                                                                            52-56.sup.g         58                                                                                ##STR99## CH.sub.3                                                                           NO.sub.2                                                                            ##STR100##                 CH.sub.3                                                                            51-55.sup.h         59                                                                                ##STR101##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR102##                 CH.sub.3                                                                            59-63.sup.i         60                                                                                ##STR103##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR104##                 CH.sub.3                                                                            65-72.sup.j         61                                                                                ##STR105##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR106##                 160-178.sup.k             62                                                                                ##STR107##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR108##                 CH.sub.3                                                                           197-200.sup. l                                                                (dec)                63                                                                                ##STR109##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR110##                 CH.sub.3                                                                            57-62.sup.m         64                                                                                ##STR111##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR112##                 CH.sub.3                                                                           glassy solid.sup.                                                             n                    65                                                                                ##STR113##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR114##                 CH.sub.3                                                                           glassy solid.sup.                                                             o                    66                                                                                ##STR115##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR116##                 CH.sub.3                                                                            58-63.sup.p         67                                                                                ##STR117##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR118##                 CH.sub.3                                                                           glassy  solid.sup                                                             .q                   68                                                                                ##STR119##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR120##                 CH.sub.3                                                                           glassy solid.sup.                                                             r                    69                                                                                ##STR121##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR122##                 CH.sub.3                                                                           glassy solid.sup.                                                             s                    70                                                                                ##STR123##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR124##                 CH.sub.3                                                                           glassy solid.sup.                                                             t                    71                                                                                ##STR125##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR126##                 CH.sub.3                                                                           glassy solid.sup.                                                             u                    72                                                                                ##STR127##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR128##                 CH.sub.3                                                                           glassy solid.sup.                                                             v                    73                                                                                ##STR129##                                                                               CH.sub.3                                                                          NO.sub.2                                                                            ##STR130##                 CH.sub.3                                                                            63-66.sup.w         74                                                                                ##STR131##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR132##                 CH.sub.3                                                                            62-65.sup.x         75                                                                                ##STR133##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR134##                 CH.sub.3                                                                            glassy solid.sup                                                             .y                   76                                                                                ##STR135##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR136##                 CH.sub.3                                                                           glassy solid.sup.                                                             z                    77                                                                                ##STR137##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR138##                 CH.sub.3                                                                           glassy solid.sup.                                                             aa                   78                                                                                ##STR139##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR140##                 CH.sub.3                                                                           glassy solid.sup.                                                             bb                   79                                                                                ##STR141##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR142##                 CH.sub.3                  80                                                                                ##STR143##                                                                              CH.sub.3                                                                           CONH.sub.2                                                                          ##STR144##                 CH.sub.3                  81                                                                                ##STR145##                                                                               ##STR146##                                                                              ##STR147##                 CH.sub.3                  82                                                                                ##STR148##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR149##                 CN                        83                                                                                ##STR150##                                                                              CH.sub.2 OH                                                                        NO.sub.2                                                                            ##STR151##                 CH.sub.3                  84                                                                                ##STR152##                                                                              CH.sub.3                                                                           H                                                                                   ##STR153##                 CH.sub.3                  85                                                                                ##STR154##                                                                              CH.sub.3                                                                           CN                                                                                  ##STR155##                 CH.sub.3                  86                                                                                ##STR156##                                                                              CH.sub.3                                                                           H                                                                                   ##STR157##                 CN                        87                                                                                ##STR158##                                                                               ##STR159##                                                                              ##STR160##                 CH.sub.3                  88                                                                                ##STR161##                                                                              C.sub.2 H.sub.5                                                                    NO.sub.2                                                                            ##STR162##                 CH.sub.3                  89                                                                                ##STR163##                                                                              C.sub.3 H.sub.7                                                                    NO.sub.2                                                                            ##STR164##                 C.sub.3 H.sub.7           90                                                                                ##STR165##                                                                              CH.sub.2 OH                                                                        CN                                                                                  ##STR166##                 CH.sub.3                  91                                                                                ##STR167##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR168##                 CH.sub.2 OH               92                                                                                ##STR169##                                                                               ##STR170##                                                                              ##STR171##                 CN                        93                                                                                ##STR172##                                                                              CH.sub.2 OH                                                                        CN                                                                                  ##STR173##                 CH.sub.3                  94                                                                                ##STR174##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR175##                 CH.sub.3                  95                                                                                ##STR176##                                                                              C.sub.2 H.sub.5                                                                    NO.sub.2                                                                            ##STR177##                 C.sub.2 H.sub.5           96                                                                                ##STR178##                                                                              CN   CN                                                                                  ##STR179##                 CH.sub.3                  97                                                                                ##STR180##                                                                              CH.sub.3                                                                           NO.sub.2                                                                            ##STR181##                 CH.sub.3                  98                                                                                ##STR182##                                                                               ##STR183##                                                                              ##STR184##                 C.sub.2 H.sub.5           99                                                                                ##STR185##                                                                              CH.sub.2 OH                                                                        NO.sub.2                                                                            ##STR186##                 CH.sub.2 OH               100                                                                               ##STR187##                                                                              CH.sub.3                                                                           CONH.sub.2                                                                          ##STR188##                 CH.sub.3                  __________________________________________________________________________    Footnotes for Table 2                                                         .sup.a1 H-NMR(200MHz, CDCl.sub.3)δ1.55(m, 4H; 2.35(s, 3H); 2.38(m,      2H); 2.54(s, 3H); 2.63(m, 4H); 3.10(m, 4H);                                   3.87(s, 3H); 4.08(t, 2H, J=6Hz); 5.81(s, 1H); 6.95(m, 3H); 7.35-7.50(m,       4H); 7.69(d, 1H, J=9Hz). Mass                                                 Spectrum: 563(M+1), 591(M+29).                                                .sup.b1 H-NMR(200MHz, CDCl.sub.3)δ1.50(m, 2H); 1.61(m, 2H); 2.38(s,     3H); 2.40(m, 1H); 2.53(s, 3H); 2.63(m, 4H);                                   3.10(m, 4H); 3.87(s, 3H); 4.08(t, 2H, J=6Hz); 5.38(s, 1H); 6.85-7.08(m,       4H); 7.25(m, 1H); 7.39(s, 1H); 7.74(d,                                        1H, J=8Hz); 8.42(d, 1H, J=3Hz); 8.50(d, 1H, J=2Hz). IR(KBr): 2940, 2816,      1705, 1646, 1501, 1446, 1310, 1272,                                           1225 cm.sup.-1. Mass Spectrum: 522(M+1), 550(M+29), 247(C.sub.15 H.sub.23     N.sub.2 O). m.p.:                                                             155-160° C.                                                            .sup.c see text for spectral data                                             .sup.d1 H-NMR(200MHz, CDCl.sub.3)δ1.53(m, 2H); 1.61(m, 2H); 2.35(m,     2H); 2.37(s, 3H); 2.46(t, 4H), J=5Hz);                                        2.55(s, 3H); 3.82(t, 4H, J=5Hz); 4.07(t, 2H, J=7Hz); 5.81(s, 1H); 6.50(t,     1H, J=5Hz); 6.53(s, 1H); 7.34(dd,                                             1H, J=6, 9Hz); 7.46(d, 1H, J=6Hz); 7.68(d, 1H, J=9Hz); 8.31(d, 2H,            J=5Hz). IR(KBr): 3500, 3308, 3212, 3084,                                      2946, 1705, 1587, 1548, 1498, 1449, 1359, 1311, 1262, 1221, 1105, 1014,       983, 797, 752 cm.sup.-1. Mass Spectrum:                                       535(M+1), 563(M+29). m.p.: 77-80° C.                                   .sup.e1 H-NMR(200MHz, CDCl.sub.3)δ2.39(s, 3H); 2.51(s, 3H); 2.71(m,     6H); 3.05(m, 4H); 3.87(s, 3H); 4.25-4.39(m,                                   2H); 5.43(s, 1H); 6.32(s, 1H); 6.84-7.03(m, 5H); 7.29(m, 2H). IR(KBr):        3510, 3315, 3230, 3090, 2940, 2830, 1708, 1650,                               1500, 1450, 1385, 1320, 1280, 1240, 1150, 1110, 1010, 750 cm.sup.-1. Mass     Spectrum: 483(M+1), 511(M+29).                                                m.p.: 57-61° C. HRMS: Calcd: 482.2165; Found: 482.2154                 .sup.f1 H-NMR(200MHz, CDCl.sub.3)δ2.39(s, 3H); 2.52(s, 3H); 2.53(m,     4H); 2.67(m, 2H); 3.80(t, 4H, J=5Hz);                                         4.20(m, 1H); 4.36(m, 1H); 5.42(s, 1H); 6.08(s, 1H); 6.32(s, 1H); 6.49(t,      1H, J=5Hz); 7.28(m, 2H); 8.31(d, 2H,                                          J=5Hz). IR(KBr): 3500, 3302, 3100, 2950, 2820, 1700, 1685, 1653, 1586,        1548, 1497, 1450, 1360, 1313, 1260, 1229,                                     1151, 1106, 1017, 984, 797 cm.sup.-1. Mass Spectrum: 455(M+1),                483(M+29).                                                                    m.p.: 50-54° C. HRMS: Calcd: 454.1964; Found: 454.1969                 .sup.g1 H-NMR(200MHz, CDCl.sub.3)δ1.51-1.70(m, 4H); 2.37(s, 3H);        2.39(m, 2H); 2.51(s, 3H); 2.61(m, 4H);                                        3.09(m, 4H); 3.85(s, 3H); 3.87(s, 3H); 4.14(m, 2H); 5.29(s, 1H); 5.86(m,      1H); 5.96(m, 2H); 6.42(t, 1H, J=2Hz);                                         6.84-7.00(m, 4H). IR(KBr): 3500, 3310, 3093, 2943, 2818, 1700, 1684,          1652, 1500, 1456, 1380, 1313, 1221, 1102,                                     1013, 814, 750 cm.sup.-1. Mass Spectrum: 524(M+1), 552(M+29). m.p.:           52-56° C.                                                              .sup.h1 H-NMR(200MHz, CDCl.sub.3)δ1.48-1.66(m, 4H); 2.35(m, 2H);        2.37(s, 3H); 2.46(m, 4H); 2.52(s, 3H);                                        3.80(m, 4H); 3.84(s, 3H); 4.12(m, 2H); 5.28(s, 1H); 5.86(m, 1H); 5.97(m,      2H); 6.42(m, 1H); 6.47(t, 1H, J=5Hz);                                         8.32(d, 2H, J=5Hz). IR(KBr): 3500, 3310, 3210, 3092, 2943, 2851, 1700,        1684, 1653, 1586, 1549, 1497, 1448,                                           1388, 1360, 1311, 1290, 1262, 1220, 1101, 1013, 983, 797, 703 cm.sup.-1.      Mass Spectrum: 496(M+1),                                                      524(M+29). m.p.: 51-55° C.                                             .sup.i1 H-NMR(200MHz, CDCl.sub.3)δ2.40(s, 3H); 2.53(s, 3H);             2.66-2.79(m, 6H); 3.00-3.17(m, 4H);                                           3.86(s, 3H); 4.17-4.43(m, 2H); 5.63(s, 1H); 6.07(s, 1H); 6.18(m, 1H);         6.26(m, 1H); 6.82-7.07(m, 4H);                                                7.23(m, 1H). IR(KBr): 3500, 3310, 3230, 3075, 2942, 2822, 1701, 1684,         1652, 1500, 1456, 1381, 1316, 1272,                                           1225, 1150, 1103, 1011, 800, 747 cm.sup.-1. Mass Spectrum; 483(M+1),          511(M+29). m.p.                                                               59-63° C. HRMS: Calcd: 482.2165; Found: 482.2164                       .sup.j1 H-NMR(200MHz, CDCl.sub.3)δ2.40(s, 3H); 2.53(m, 4H); 2.54(s,     3H); 2.68(t, 2H, J=6Hz);                                                      3.80(m, 4H); 4.23-4.35(m, 2H); 5.62(s, 1H); 6.09(s, 1H); 6.15(d, 1H,          J=3Hz), 6.25(m, 1H); 6.49(t, 1H,                                              J=5Hz); 7.23(d, 1H, J=2Hz); 8.30(d, 2H, J=5Hz). IR(KBr): 3546, 3310,          3094, 2941, 2822, 1706, 1648,                                                 1586, 1548, 1490, 1449, 1360, 1314, 1261, 1224, 1152, 1102, 1010, 982,        797, 739 cm.sup.-1. Mass                                                      Spectrum: 455(M+1), 483(M+29). m.p.: 65-72° C. HRMS: Calcd:            454.1964; Found: 454.1969                                                     .sup.k1 H-NMR(200MHz, CDCl.sub.3)δ2.40(s, 3H); 2.54(s, 3H); 2.64(m,     6H); 3.05(m, 4H); 3.87(s, 3H);                                                4.22(t, 2H, J=6Hz); 5.42(s, 1H); 6.84-7.00(m, 4H); 7.08(m, 1H); 7.21(m,       1H); 7.77(d, 1H,                                                              J=8Hz); 8.42(m, 1H); 8.52(d, 1H, J=2Hz). IR(KBr): 3500, 3296, 3174, 3057,     2933, 2829, 1705, 1642, 1592,                                                 1500, 1450, 1377, 1309, 1270, 1222, 1145, 1101, 1021, 753 cm.sup. -1.         Mass Spectrum: 494(M+1),                                                      522(M+29). m.p.: 160-178° C.                                           .sup.l1 H-NMR(200MHz, CDCl.sub.3)δ2.39(s, 3H); 2.48(m, 4H); 2.53(s,     3H); 2.60(t, 2H, J=6Hz);                                                      3.77(m, 4H); 4.21(m, 2H); 5.41(s, 1H); 6.49(t, 1H, J=5Hz); 7.22(m, 2H);       7.76(d, 1H, J=8Hz); 8.30(d,                                                   2H, J=5Hz); 8.41(m, 1H); 8.52(d, 1H, J=2Hz). IR(KBr): 3500, 3190, 3062,       2936, 1682, 1587, 1546, 1506,                                                 1307, 1234, 1105, 1016, 984, 780 cm.sup.-1. Mass Spectrum: 466(M+1),          494(M+29). m.p.:                                                              197-200° C. (dec).                                                     .sup.m1 H-NMR(200MHz, CDCl.sub.3)δ1.36-1.69(m, 4H); 2.38(m, 2H);        2.40(s, 3H); 2.53(s, 3H); 2.62(m, 4H);                                        3.08(m, 4H); 3.87(s, 3H); 4.14(m, 2H); 5.77(s, 1H); 6.08(s, 1H);              6.82-7.03(m, 4H); 6.86(m, 2H); 7.09(m, 1H).                                   IR(KBr): 3500, 3304, 3065, 2942, 2817, 1704, 1642, 1501, 1314, 1272,          1228, 1103, 749 cm.sup.-1.                                                    Mass Spectrum: 527(M+1), 555(M+29). m.p.: 57-62° C.                    .sup.n1 H-NMR(200MHz, CDCl.sub.3)δ1.51(m, 2H); 1.66(m, 2H); 2.36(m,     2H); 2.40(s, 3H); 2.46(m, 4H);                                                2.53(s, 3H); 3.82(m, 4H); 4.16(m, 2H); 5.76(s, 1H); 6.43(s, 1H); 6.46(m,      1H); 6.87(m, 2H); 7.10(m, 1H);                                                8.30(m, 2H). IR(KBr): 3500, 3306, 3068, 2939, 1706, 1586, 1548, 1492,         1359, 1312, 1226, 1012, 982, 795 cm.sup.-1.                                   Mass Spectrum: 499(M+1), 527(M+29).                                           .sup.o1 H-NMR(200MHz, CDCl.sub.3)δ2.40(s, 3H); 2.52(s, 3H); 2.69(m,     6H); 3.05(m, 4H); 3.87(s, 3H);                                                4.22-4.33(m, 2H); 5.60(s, 1H); 6.06(s, 1H); 6.84-7.00(m, 3H); 7.03(m,         2H); 7.12(m, 2H). IR(KBr):                                                    3500, 3309, 3096, 2941, 2822, 1703, 1500, 1314, 1226, 1104, 1015, 749         cm.sup.-1. Mass Spectrum:                                                     499(M+1), 527(M+29).                                                          .sup.p1 H-NMR(200MHz, CDCl.sub.3)δ2.40(s, 3H); 2.46(m, 4H); 2.52(s,     3H); 2.64(t, 2H, J=6Hz);                                                      3.78(m, 4H); 4.18(m, 1H); 4.34(m, 1H); 5.59(s, 1H); 6.01(s, 1H); 6.48(t,      1H, J=5Hz); 7.03(m, 1H);                                                      7.09(s, 1H); 7.17(m, 1H); 8.29(d, 2H, J=5Hz). IR(KBr): 3500, 3312, 3094,      2943, 1703, 1586, 1548, 1492,                                                 1360, 1311, 1262, 1225, 1104, 1015, 983 cm.sup.-1. Mass Spectrum:             471(M+1), 499(M+29).                                                          m.p.: 58-63° C. HRMS: Calcd: 470.1736; Found: 470.1731                 .sup.q1 H-NMR(200MHz, CDCl.sub.3)δ1.49-1.61(m, 2H); 1.62-1.73(m,        2H); 2.37(s, 3H); 2.44(m, 2H);                                                2.50(s, 3H); 2.62(m, 4H); 3.10(m, 4H); 3.87(m, 3H); 4.16(m, 2H); 5.41(s,      1H); 6.22(s, 1H); 6.28(s, 1H);                                                6.84-7.04(m, 4H); 7.27(m, 2H); IR(KBr): 3310, 2944, 2818, 1703, 1652,         1500, 1315,                                                                   1230, 1106, 1017, 750 cm.sup.-1. Mass Spectrum. 511(M+1), 539(M+29).          .sup.r1 H-NMR(200MHz, CDCl.sub.3)δ1.50-1.62(m, 2H); 1.68(m, 2H);        2.33-2.44(m, 2H); 2.38(s, 3H);                                                2.48(m, 4H); 2.50(s, 3H); 3.82(t, 4H, J=5Hz); 4.07-4.19(m, 2H); 5.41(s,       1H); 6.28(d, 1H, J=1Hz);                                                      6.36(s, 1H); 6.48(t, 1H, J=5Hz); 7.24(s, 1H); 8.29(d, 2H, J=5Hz).             IR(KBr): 3312, 2950, 1702,                                                    1586, 1548, 1492, 1359, 1313, 1229, 1106, 1015, 753 cm.sup.-1. Mass           Spectrum: 482(M.sup.+).                                                       .sup.s1 H-NMR(200MHz, CDCl.sub.3)δ1.52-1.73(m, 4H); 2.39(s, 3H);        2.42(m, 2H); 2.54(s, 3H);                                                     2.64(m, 4H); 3.10(m, 4H); 3.87(s, 3H); 4.15(m, 2H);                           5.61(s, 1H); 6.10(d, 1H, J=3Hz); 6.17(s, 1H); 6.24(m, 1H); 6.84-7.01(m,       4H); 7.21(d, 1H, J=2Hz).                                                      IR(film); 3312, 2945, 2819, 1703, 1500, 1316, 1230, 1011, 750 cm.sup.-1.      Mass Spectrum: (M+1),                                                         (M+29). HRMS: Calcd: 510.2478; Found: 510.2466                                .sup.t1 H-NMR(200MHz, CDCl.sub.3)δ1.54(m, 2H); 1.60-1.71(m, 2H);        2.35-2.42(m, 2H); 2.39(s, 3H);                                                2.48(t, 4H, J=5Hz); 2.54(s, 3H); 3.82(t, 4H, J=5Hz); 4.15(m, 2H); 5.61(s,     1H); 6.10(d, 1H, J=3Hz);                                                      6.16(s, 1H); 6.24(t, 1H, J=3Hz); 6.47(t, 1H, J=5Hz); 7.22(s, 1H); 8.30(d,     2H, J=5Hz).                                                                   IR(film): 3314, 2947, 1704, 1586, 1548, 1494, 1359, 1315, 1224, 1011,         984, 752 cm.sup.-1. Mass Spectrum:                                            483(M+1), 511(M+29).                                                          .sup.u1 H-NMR(200MHz, CDCl.sub.3)δ1.54(m, 2H); 1.64(m, 2H); 2.33(s,     3H); 2.40(t, 2H, J=7Hz); 2.47(s, 3H);                                         2.62(s, 4H); 3.09(s, 4H); 3.85(s, 3H); 4.12(d, 2H<J=5Hz); 5.56(s, 1H);        6.84-7.01(m, 4H); 7.03(m, 2H);                                                7.15(m, 1H); 7.36(s, 1H). IR(film): 3314, 2943, 2818, 1702, 1500, 1312,       1226, 1014, 751 cm.sup.-1.                                                    Mass Spectrum: 527(M+1), 555(M+29).                                           .sup.v1 H-NMR(200MHz, CDCl.sub.3)δ1.50(m, 2H); 1.64(m, 2H); 2.35(t,     2H, J=7Hz); 2.40(s, 3H); 2.46(t, 4H,                                          J=5Hz); 2.52(s, 3H); 3.82(t, 4H, J=5Hz); 4.12(m, 2H); 5.57(s, 1H);            5.99(s, 1H); 6.48(t, 1H, J=5Hz);                                              7.01(m, 2H); 7.17(m, 1H); 8.30(d, 2H, J=5Hz). IR(KBr): 3314, 3097, 2946,      1702, 1586, 1547, 1492, 1359, 1312,                                           1226, 1014, 983, 796 cm.sup.-1. Mass Spectrum: 499(M+1), 527(M+29). HRMS:     Calcd: 498.2049; -Found: 498.2060.                                            .sup.w1 H-NMR(200MHz, CDCl.sub.3)δ2.43(s, 3H); 2.48(m, 4H); 2.53(s,     3H); 2.66(t, 2H, J=5Hz); 3.77(m, 4H);                                         4.23(m, 1H); 4.33(m, 1H); 5.78(s, 1H); 6.00(s, 1H); 6.48(t, 1H, J=5Hz);       6.88(m, 1H); 6.92(d, 1H, J=2Hz);                                              7.11(m, 1H); 8.29(d, 2H, J=5Hz). IR(KBr): 3308, 3089, 2941, 1705, 1586,       1548, 1491, 1360, 1311, 1227, 1014,                                           983 cm.sup.-1. Mass Spectrum: 471(M+1), 499(M+ 29). m.p.: 63-66°       C. HRMS: Calcd: 470.1736;                                                     Found: 470.1735.                                                              .sup.x1 H-NMR(200MHz, CDCl.sub.3)δ2.43(s, 3H); 2.53(s, 3H); 2.66(m,     4H); 2.70(m, 2H); 3.05(m, 4H); 3.87(m, 3H);                                   4.26-4.34(m, 2H); 5.79(s, 1H); 6.03(s, 1H); 6.84-7.03(m, 6H); 7.11(m,         1H), IR(KBr): 3311, 3068, 2940, 2821, 1705,                                   1500, 1381, 1314, 1230, 1015, 750 cm.sup.-1. Mass Spectrum:                   499(M+1), 527(M+29). m.p.: 62-65° C. HRMS: Calcd: 498.1936; Found:     498.1942.                                                                     .sup.y1 H-NMR(200MHz, CDCl.sub.3)δ2.38(s, 3H); 2.56(s, 3H);             2.57-2.67(m, 6H); 3.03(m, 4H); 3.87(s, 3H);                                   4.19(m, 2H); 5.82(s, 1H); 6.30(s, 1H); 6.85-7.04(m, 4H); 7.34(m, 1H);         7.52(d, 1H, J=7Hz); 7.68(d, 1H, J=9Hz).                                       IR(KBr): 3323, 3094, 2941, 2820, 1707, 1500, 1312, 1223, 1015, 750            cm.sup.-1.                                                                    Mass Spectrum: 535(M+1), 563(M+29). HRMS: Calcd: 534.2227; Found:             534.2219.                                                                     .sup.z1 H-NMR(200MHz, CDCl.sub.3)δ2.38(s, 3H); 2.49(t, 4H, J=5Hz);      2.56(s, 3H); 2.61(m, 2H); 3.77(t, 4H,                                         J=5Hz); 4.20(m, 2H); 5.82(s, 1H); 6.25(s, 1H); 6.49(t, 1H, J=5Hz);            7.34(dd, 1H, J=7, 9Hz); 7.50(d, 1H, J=7Hz);                                   7.69(d, 1H, J=9Hz); 8.31(d, 2H, J=5Hz). IR(KBr): 3300, 3100, 2950,            2830, 1710, 1585, 1545, 1500, 1360, 1305, 1230, 1100, 1012, 980, 748          cm.sup.- 1. Mass Spectrum: 507(M+1). 535(M+29).                               .sup.aa see text for spectral data.                                           .sup.bb1 H-NMR(200MHz, CDCl.sub.3)δ2.38(s, 3H); 2.49(t, 4H, J=5Hz);     2.52(s, 3H); 2.62(t, 2H, J=6Hz); 3.78(t, 4H,                                  J=5Hz); 3.86(s, 3H); 4.26(m, 2H); 5.30(s, 1H); 5.87(dd, 1H, J=2, 3Hz);        5.92(s, 1H); 5.97(t, 1H, J=3Hz); 6.42(t, 1H,                                  J=2Hz); 6.49(t, 1H, J=5Hz); 8.30(d, 2H, J=5Hz). IR(KBr): 3319, 3096,          2941, 2850, 1704, 1586, 1548, 1492, 1360, 1310, 1221, 1102, 1014, 983         cm.sup.-1. Mass Spectrum: 468(M+1),                                           496(M+29). HRMS: Calcd: 467.2281; Found: 467.2267.                        

Utility

The compounds of this invention have been found to possess both Ca²⁺channel activity, preferably Ca²⁺ agonist activity, andalphal-antagonist activity. These pharmacological properties of thecompounds of this invention were evaluated in the followingpharmacological experiments.

Determination of Affinity for alpha₁ -Adrenoceptors

The [³ H]-prazosin binding assay was carried out according to the methoddescribed by Timmermans, P. B. M. W. M., Schoop, A. M. C., and VanZwieten, P. A., Biochem. Pharmacol., 31, 899-905, (1982). The reactionmixture contained partially purified rat brain membranes (source ofalphaladrenoceptors), 0.2 nM [³ H]-prazosin with or without potentialdisplacer in Tris buffer. The mixture was incubated for 60 minutes at25° C. and subsequently terminated by rapid filtration through glassfiber-filter. Receptor-bound [³ H]-prazosin trapped in the filter wasquantitated by scintillation counting. The inhibitory concentration(IC₅₀) of potential displacer which gives 50% displacement of the totalspecifically bound [³ H]-prazosin is presented as a measure of theaffinity of such compound for the alpha₁ -adrenoceptor.

Determination of Affinity for Calcium Channels

[³ H]-Nitrendipine binding assay was carried out according to the methoddescribed by G. T. Bolger, et al., Biochem. Biophys. Res. Comm., 104,1604-1609, (1982). The reaction mixture contained rat cardiac microsomes(source of Ca²⁺ channels), 0.5 nM [³ H]-nitrendipine with or withoutpotential displacer in Tris buffer. The mixture was incubated for 60minutes at 25° C. and subsequently terminated by rapid filtrationthrough a glass fiber-filter. Membrane-bound [³ H]-nitrendipine trappedin the filter was quantitated by scintillation counting. The inhibitoryconcentration (IC₅₀) of potential displacer which gives 50% displacementof the total specifically bound [³ H]-nitrendipine is presented as ameasure of the affinity of such compound for the Ca²⁺ channel.

The results from the above two in vitro assays are summarized in Table3.

                  TABLE 3                                                         ______________________________________                                        Binding Affinity Data for Calcium and                                         Alpha.sub.1 -adrenoceptors                                                                [.sup.3 H]-Nitrendipine                                                                    [.sup.3 H]-Prazosin                                  Example No. binding IC.sub.50 [M]                                                                      binding IC.sub.50 [M]                                ______________________________________                                         1          6.0 × 10.sup.-7                                                                      1.3 × 10.sup.-7                                 2          1.5 × 10.sup.-6                                                                      1.9 × 10.sup.-6                                 3          2.4 × 10.sup.-7                                                                      6.3 × 10.sup.-8                                 4          8.9 × 10.sup.-7                                                                      2.0 × 10.sup.-8                                 5          6.8 × 10.sup.-7                                                                      2.2 × 10.sup.-6                                 6          3.6 × 10.sup.-7                                                                      9.0 × 10.sup.-7                                 7          6.5 × 10.sup.-7                                                                      1.9 × 10.sup.-6                                 8          5.8 × 10.sup.-7                                                                      1.5 × 10.sup.-5                                 9          9.5 × 10.sup.-7                                                                      5.2 × 10.sup.-6                                10          1.2 × 10.sup.-6                                                                      7.2 × 10.sup.-6                                11          3.6 × 10.sup.-7                                                                      5.3 × 10.sup.-6                                51          1.1 × 10.sup.-7                                                                      1.2 × 10.sup.-7                                52          3.9 × 10.sup.-6                                                                      5.2 × 10.sup.-8                                53          4.4 × 10.sup.-6                                                                      4.0 × 10.sup.-7                                54          2.9 × 10.sup.-7                                                                      8.2 × 10.sup.-7                                55          5.1 × 10.sup.-6                                                                      1.0 × 10.sup.-7                                56          4.3 × 10.sup.-6                                                                      5.2 × 10.sup.-6                                57          1.3 × 10.sup.-6                                                                      3.3 × 10.sup.-8                                58          1.8 × 10.sup.-6                                                                      7.5 × 10.sup.-7                                59          1.5 × 10.sup.-6                                                                      1.0 × 10.sup.-7                                60          2.0 × 10.sup.-6                                                                      5.9 × 10.sup.-6                                61          1.3 × 10.sup.-6                                                                      2.5 × 10.sup.-8                                62          3.7 × 10.sup.-6                                                                      >1.0 × 10.sup.-6                               63          2.2 × 10.sup.-6                                                                      6.0 × 10.sup.-8                                64          1.2 × 10.sup.-6                                                                      1.2 × 10.sup.-6                                65          8.6 × 10.sup.-7                                                                      1.8 × 10.sup.-7                                66          9.5 × 10.sup.-7                                                                      6.0 × 10.sup.-6                                67          3.5 × 10.sup.-6                                                                      6.3 × 10.sup.-8                                68          2.7 × 10.sup.-6                                                                      8.5 × 10.sup.-7                                69          2.0 × 10.sup.-6                                                                      3.5 × 10.sup.-8                                70          2.0 × 10.sup.-6                                                                      8.4 × 10.sup.-7                                71          1.7 × 10.sup.-6                                                                      7.8 × 10.sup.-8                                72          1.6 × 10.sup.-6                                                                      1.0 × 10.sup.-6                                73          2.4 × 10.sup.-6                                                                      4.9 × 10.sup.-6                                74          1.9 × 10.sup.-6                                                                      1.2 × 10.sup.-7                                75          8.5 × 10.sup.-8                                                                      4.7 × 10.sup.-7                                76          8.5 × 10.sup.-8                                                                      1.7 × 10.sup.-5                                77          1.1 × 10.sup.-6                                                                      1.1 × 10.sup.-7                                78          1.7 × 10.sup.-6                                                                      3.3 × 10.sup.-6                                ______________________________________                                    

Protocol for Positive Inotropic Effect in Guinea Pig Left Atria

Guinea pigs are killed by cervical dislocation. The left atria areremoved and mounted at 1 gm resting tension in tissue baths containingoxygenated Krebs bicarbonate solution which is kept at 37° C. The leftatria are electrically paced at 2 Hz with square wave pulses of 1 msecduration. The voltage is set at 1.5×threshold level.

After a one hour equilibration period, control values for developedtension (DT, gm) are recorded. Test compounds are then added to thebaths, in a cumulative manner to a maximum concentration of 10⁻⁴, toobtain a concentration-response curve. Treatment values of DT areobtained after the drug effect has reached a plateau and the exposuretime for each concentration is 5-8 minutes. Percent change of thetreatment value from the control value is calculated at eachconcentration of the test compound. The results are shown in Table 4below.

                  TABLE 4                                                         ______________________________________                                                                    Intrinsic                                         Example No.     EC.sub.50 (M).sup.a                                                                       Activity.sup.b                                    ______________________________________                                        Control-Bay K8644                                                                             1.5 × 10.sup.-7                                                                     100                                                1              5.0 × 10.sup.-6                                                                     188                                                2              9.6 × 10.sup.-5                                                                     144                                                3              1.0 × 10.sup.-6                                                                     89                                                 4              --          43                                                 5              3.0 × 10.sup.-6                                                                     269                                                6              2.0 × 10.sup.-6                                                                     207                                                7              1.2 × 10.sup.-5                                                                     149                                                8              1.5 × 10.sup.-5                                                                     113                                                9              5.3 × 10.sup.-5                                                                     62                                                10              2.8 × 10.sup.-6                                                                     55                                                11              4.3 × 10.sup.-5                                                                     68                                                51              1.1 × 10.sup.-5                                                                     175                                               52              --          35                                                53              2.5 × 10.sup.-5                                                                     189                                               54              >1.0 × 10.sup.-4                                                                    21                                                55              1.0 × 10.sup.-6                                                                     169                                               56              4.3 × 10.sup.-7                                                                     171                                               57              2.3 × 10.sup.-6                                                                     110                                               58              8.4 × 10.sup.-7                                                                     195                                               59              2.7 × 10.sup.-6                                                                     98                                                60              1.6 × 10.sup.- 6                                                                    140                                               61              1.5 × 10.sup.-6                                                                     164                                               62              >1.0 × I0.sup.-4                                                                    48                                                63              1.2 × 10.sup.-5                                                                     75                                                64              3.4 × 10.sup.-6                                                                     76                                                65              1.0 × 10.sup.-6                                                                     225                                               66              8.5 × 10.sup.-7                                                                     210                                               67              2.4 × 10.sup.-5                                                                     86                                                68              3.7 × 10.sup.-6                                                                     147                                               69              6.2 × 10.sup.-5                                                                     60                                                70              5.0 × 10.sup.-6                                                                     132                                               71              --          40                                                72              1.2 × 10.sup.-5                                                                     70                                                73              9.8 × 10.sup.-7                                                                     84                                                74              6.3 × 10.sup.-7                                                                     173                                               75              4.0 × 10.sup.-7                                                                     82                                                76              5.6 × 10.sup.-8                                                                     156                                               77              2.3 × 10.sup.-7                                                                     240                                               78              5.8 × 10.sup.-7                                                                     231                                               ______________________________________                                         .sup.a EC.sub.50 (m) = concentration that increases DT by 50% above the       control DT.                                                                   .sup.b Intrinsic Activity is a ratio of the maximum effect of the test        compound to that of Bay K8644 and expressed in percent.                  

The foregoing test results suggest that compounds of this invention haveutility in the treatment of congestive heart failure.

Dosage Forms

Compounds of this invention can be administered to treat saiddeficiencies by any means that produces contact of the active agent withthe agent's site of action in the body of the mammal. The compounds canbe administered by any conventional means available for use inconjunction with pharmaceuticals, either as individual therapeuticagents or in a combination of therapeutic agents. They can beadministered alone, but are generally administered with a pharmaceuticalcarrier selected on the basis of the chosen route of administration andstandard pharmaceutical practice.

The dosage administered will, of course, vary depending on the use andknown factors such as the pharmacodynamic characteristics of theparticular agent, and its mode and route of administration; age, health,and weight of the recipient; nature and extent of symptoms, kind ofconcurrent treatment, frequency of treatment, and the effect desired.For use in the treatment of said diseases, a daily dosage of activeingredient can be about 50 to 1000 mg.

Dosage forms (compositions) suitable for administration contain about 1milligram to about 100 milligrams of active ingredient per unit. Inthese pharmaceutical compositions the active ingredient will ordinarilybe present in an amount of about 0.5-95% by weight based on the totalweight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions or parenterally, in sterile liquiddosage forms. Alternatively it can be administered sublingually bytablets, gels, pastes, patches or lozenges.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, starch, cellulose derivatives, magnesium stearate,stearic acid, and the like. Similar diluents can be used to makecompressed tablets. Both tablets can be sugar coated to mask anyunpleasant taste and protect the tablet from the atmosphere, or entericcoated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, A. Osol, a standard reference text in thisfield.

Useful pharmaceutical dosage forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil is prepared as injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules arewashed and dried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 milligrams of active ingredients, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings may beapplied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol. The solution is made to volume with water forinjection and sterilized.

Suspension

An aqueous suspension is prepared for oral administration so that each 5milliliters contain 100 milligrams of finely divided active ingredient,100 milligrams of sodium benzoate, 1.0 grams of sorbitol solution,U.S.P., and 0.025 milliliters of vanillin.

What is claimed is:
 1. A compound of the formula: ##STR189## or apharmaceutically acceptable salt thereof or an optically active isomeror N-oxide thereof wherein:R² and R⁶ independently are alkyl of 1-4carbon atoms, CN, CH₂ OH or CH₂ OCH₂ CH₂ NH₂ ; R³ independently is NO₂,H, CN, CONH₂, Cy, when R⁵ is CHO, COCH₃, CO₂ CH₂ CHOHC₆ H₅, CO₂CH(OCH₃)CH₅, NO₂, CONHC₆ H₅ or an alkyl ester of 1-10 carbon atoms, is:##STR190## R¹ and R⁹ independently are H, alkyl of 1-4 carbon atoms,haloalkyl of 1-4 carbon atoms, alkoxy of 1-10 carbon atoms, halogen, orNO₂ ; X is SO, SO₂, NR⁴, O, S or N→O; Y is CH₂, ##STR191## Z is##STR192## R⁴ is H or an alkyl group of 1-4 carbon atoms; R⁷ is##STR193## A is a straight or branched alkyl, alkenyl, or alkynyl chainor --(CH₂)_(n) CHOHCH₂ --; R⁸ is ##STR194## Ar is phenyl optionallysubstituted with one or two substituents independently selected from thegroup consisting of: alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbonatoms, alkoxy of 1-4 carbon atoms, halogen, or NO₂, provided that Ar isnot 4-fluorophenyl; n is independently 1-4; AND p is 1 to 10with thefollowing proviso: ##STR195## and X is O, S or NH; when Cy is then, R²cannot be --(A)_(r) --NH--Q--Ar, where A is as defined above; and R⁸cannot be Ar.
 2. A compound of claim 1 wherein R² is CH₃.
 3. A compoundof claim 1 wherein R³ is NO₂.
 4. A compound of claim 1 wherein Cy is##STR196## when R⁵ is an alkyl ester of 1-4 carbon atoms.
 5. A compoundof claim 4 wherein ##STR197## where R⁵ is an alkyl ester of 1-4 carbonatoms.
 6. A compound of claim 5 wherein R¹ is H.
 7. A compound of claim5 wherein X is O or SO₂.
 8. A compound of claim 1 wherein:R² is CH₃ ; R³is NO₂ ; ##STR198## Cy is R⁵ is an alkyl ester of 1-4 carbon atoms; R¹is H; X is O or SO₂ ; and R⁷ is ##STR199##
 9. The compound of claim 1which is 1,4-dihydro-4-(2-{5-[4-(2-methoxyphenyl)-1-piperazinyl]pentyl}-3-furanyl)-2,6-dimethyl-5-nitro-3-pyridinecarboxylic acid,methyl ester.
 10. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim
 1. 11. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of claim
 2. 12. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim
 3. 13. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 4.14. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundof claim
 5. 15. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim
 6. 16. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of claim
 7. 17. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim
 8. 18. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of the compound of claim9.
 19. A method for treating congestive heart failure in a mammal whichcomprises administering to the mammal a therapeutically effective amountof a compound of claim
 1. 20. A method for treating cogestive heartfailure in a mammal which comprises administering to the mammal atherapeutically effective amount of a compound of claim
 2. 21. A methodfor treating cogestive heart failure in a mammal which comprisesadministering to the mammal a therapeutically effective amount of acompound of claim
 3. 22. A method for treating cogestive heart failurein a mammal which comprises administering to the mammal atherapeutically effective amount of a compound of claim
 4. 23. A methodfor treating cogestive heart failure in a mammal which comprisesadministering to the mammal a therapeutically effective amount of acompound of claim
 5. 24. A method for treating cogestive heart failurein a mammal which comprises administering to the mammal atherapeutically effective amount of a compound of claim
 6. 25. A methodfor treating cogestive heart failure in a mammal which comprisesadministering to the mammal a therapeutically effective amount of acompound of claim
 7. 26. A method for treating cogestive heart failurein a mammal which comprises administering to the mammal atherapeutically effective amount of a compound of claim
 8. 27. A methodfor treating cogestive heart failure in a mammal which comprisesadministering to the mammal a therapeutically effective amount of thecompound of claim 9.